HUMAN VACCINES & IMMUNOTHERAPEUTICS

2022, VOL. 18, NO. 1, e1866950 (12 pages)

https://doi.org/10.1080/21645515.2020.1866950

REVIEW

Vaccination in preterm and low birth weight infants in India

Santosh Soansa, Attila Mihalyib, Valerie Berlaimont c
, Shafi Kolhapure d
, Resham Dash e
, and Ashish Agrawal f

a
Paediatrics, AJ Institute of Medical Sciences, Mangalore, India; bMedical Affairs and Clinical R&D, GSK Vaccines Europe, Wavre, Belgium; cGlobal
Medical Affairs, GSK, Wavre, Belgium; dMedical Affairs Department, GSK, Mumbai, India; eMedical Affairs Department, GSK, Bengaluru, India; fMedical
Affairs Department, GSK, Hyderabad, India

ABSTRACT ARTICLE HISTORY

In India, the high neonatal and infant mortality rate is due in part to an increasing number of preterm and Received 17 September 2020
low birth weight (LBW) infants. Given the immaturity of immune system, these infants are at an increased Revised 21 November 2020
risk of hospitalization and mortality from vaccine-preventable diseases (VPDs). In this narrative review, we Accepted 15 December 2020
screened the scientific literature for data on the risk of VPDs, vaccination delay and factors related to it in KEYWORDS
Indian preterm and LBW infants. Although routine childhood vaccinations are recommended regardless of Neonatal; preterm; low birth
gestational age or birth weight, vaccination is often delayed. It exposes these infants to a higher risk of weight; immunization; India;
infections, their associated complications, and death. After-birth complications, lack of awareness prematurity; infectious
of recommendations, vaccine efficacy and effectiveness and concerns related to safety are some of the disease; vaccination
common barriers to vaccination. Awareness campaigns might help substantiate the need for (and value
of) vaccination in preterm and LBW infants.

PLAIN LANGUAGE SUMMARY

What is the context?
● In India, the high neonatal mortality rate is due in part to an increasing number of pretern and low birth
weight intants.
● Affected infants have a poorly developed inmune system and are more susceptible to contracting
vaccine-preventable diseases.
● The Indian Academy of Pediatrics recommends vaccination according to the same schedule used for
full term infants, following chronological (not gestational) age.
● Delays in vaccinations increase the risk of preventable infections.
What is new?
● Our review of the scientific literature shows that, in India:
○ infections have more serious conseuences in preterm and low birth weight infants
○ delays to vaccinate affected infants are common, mostly due to safety and effectiveness concerns
from parents and healthcare pracitionrs.
What is the impact?
● Improving mternal nutritional status and immunization, and perinatal care could help reduce the
number of preterm and low birth weight infants.
● Combining maternal immunization with vaccination of affected infants can confer safe and effective
protection.
● Awareness campaigns for parents and healthcare practitioners could address the issue of vaccination
delay in pretern and low birth weight infants in India.

Introduction Preterm birth can be either spontaneous or induced (e.g.

Preterm birth and low birth weight (LBW) in newborns is
a source of significant global public health concern.1
Although LBW often characterizes preterm babies, the two
terms cannot be used interchangeably.2 World Health
Organization (WHO) defines preterm newborn as birth before
37 weeks of gestation and further categorizes it into extremely
preterm (<28 weeks), very preterm (28–32 weeks) and moder­
ate to late preterm (32–37 weeks).3 LBW is defined as weight at
birth of <2,500 g and is categorized into very LBW (<1,500 g)
and extremely LBW (<1,000 g).4
elective cesarean or other non-medical reasons).5,6
Correspondingly, LBW could be associated with preterm
birth, or could be due to restricted fetal growth, or
a combination of both.7 Risk factors for prematurity and
LBW include undernutrition, genetics, infections, underlying
comorbidities (e.g., diabetes), maternal history of multiple
pregnancies, chronic maternal stress induced by infections
and inflammation, socioeconomic factors, and lifestyle choices
of the mother (e.g., smoking).6,8
Preterm and LBW infants are at a higher risk of infections
and death compared to full-term and normal birth weight

CONTACT Ashish Agrawal ashish.8.agrawal@gsk.com GlaxoSmithKline Pharmaceuticals Ltd 205, 2nd Floor, 62 Navketan Building, Secunderabad, Hyderabad
500003, India.
© 2021 GlaxoSmithKline Biologicals SA. Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
e1866950-2 S. SOANS ET AL.
infants.9 The major risk factors are perinatal infections, pro­
longed hospitalization after birth, iatrogenic complications of
lifesaving therapies, low levels of circulating maternal antibo­
dies, and an immature immune system.9 Specifically, the
immaturity of the immune system is known to increase with
decreasing gestational age and birth weight.10–12 Perinatal
infections could be fatal and are associated with long-term
sequelae that can lead to impaired neuro-developmental func­
tioning, inhibited growth, chronic diseases and long-term phy­
sical health consequences.6,10–12
Increasing numbers of preterm and LBW newborns
every year could add to the disease burden on healthcare systems
and individual families, depending on the setting.1,6,8,13
According to the WHO, more than 10% of infants (i.e.,
~15 million infants per year) were born preterm and 15%–20%
of infants (i.e., >20 million infants per year) were born with LBW
in 2014–2015.1,2,14 Preterm birth directly contributes to neonatal
mortality, accounting for nearly 1 million deaths every year,1
while LBW is a major predictor of mortality and morbidity in
preterm children.1 Highest levels of neonatal mortality and
morbidity are reported in low- and middle-income countries,
with Africa and Asia being responsible for the majority of this
public health burden.15,16 In 2018, approximately 50% of all
deaths under 5 years of age were reported from just five coun­
tries: Democratic Republic of the Congo, Ethiopia, India,
Nigeria, and Pakistan. Among these countries, about 33% of
deaths were reported in Nigeria and India alone.17
The Indian context
In 2017, India recorded approximately one million deaths (20%
of the global) among children under 5 years of age.18 Of these,
0.57 million were neonatal deaths in which the reported causes
were preterm birth (27.7%), encephalopathy due to birth
asphyxia and trauma (14.5%), lower respiratory infections
(11.0%), congenital birth defects (8.6%), sepsis and other infec­
tions (6.1%), hemolytic disease and jaundice (3.2%), diarrheal
diseases (2.7%), tetanus (0.7%), other disorders (22.0%), and
other causes (3.5%).18 This situation is alarming as India
accounts for 23.4% of the global preterm births.14 Estimates
of LBW infants are notable: during 2013–2014, amongst
approximately 19 million newborns,19 68.7% were weighed at
birth and among these, 18.6% were LBW (i.e., approximately
2.43 million births).20
The majority of deaths in children under 5 years of age and
morbidity associated with infectious diseases can be averted by
timely interventions including adequate nutrition, clean water,
appropriate maternal care during pregnancy and immuniza­
tion of the mother and infant.17 The WHO and the Advisory
Committee on Vaccines and Immunization Practices of the
Indian Academy of Pediatrics (IAP) recommend that all
infants receive immunization, regardless of any restrictions
based on gestational age or birth weight, with the qualified
exception of the hepatitis B vaccine as the birth dose is not
counted toward the full schedule due to a reduced immune
response.21–23 Table 1 provides an overview of the recom­
mended vaccines in children ≤12 months of age.
Rationale of the review
Despite the existence of vaccination recommendations, several
studies in high-income countries have reported either
a significant delay or a complete lack of immunization in pre­
term infants.47–50 The situation is unlikely to be different in
India, as a high level of vaccine-preventable disease (VPD)
burden in infants or children persists.51 Within this context,
there is a need to better understand the factors and barriers
related to the absence or delay in vaccination among preterm
and LBW infants. This information could help bridge existing
knowledge gaps in the scientific community, specifically among
healthcare providers (HCPs) who are perceived as the most
trusted advisors and influencers of vaccination decisions.52
A recent publication summarizing practical issues sur­
rounding vaccination in preterm infants lends support to the
implementation of existing vaccination recommendations for
preterm and LBW infants in India.53 However, information on
the extent of vaccination delay in preterm and LBW infants has
not been previously summarized. In this review, we outline the
rationale for immunization and highlight the risks of VPDs in
preterm and LBW infants. We also provide an overview of
recommended vaccinations, with a focus on whether efficacy/
effectiveness and safety data are available in these populations.
Lastly, we present the caveats linked to different vaccination
strategies that could be utilized to mitigate the burden of VPDs
in preterm and LBW infants in India. Figure 1 elaborates onthe
findings in a form that could be shared with patients by HCPs.
Characteristics of the immune system of preterm and
LBW infants
Neonates predominantly rely on their first line of defense
(physical barrier) and then innate immune response rather
than adaptive immune response. At birth, both immune
defense mechanisms are immature.54 This immune system
immaturity is amplified in infants born preterm and in those
with LBW, due to several deficiencies (Table 2).
Defense against pathogens consists of physical barriers, such
as keratinized skin and mucous membranes lining the respira­
tory and gastrointestinal tracts, and chemical barriers contain­
ing various enzymes and other substances that elicit a direct
antimicrobial action or inhibit microbial adherence to body
surfaces.55 Compared to full-term infants, this barrier is unde­
veloped in preterm and LBW infants, making it susceptible to
ruptures and therefore serving as an inefficient defense
barrier.55 Furthermore, antimicrobial peptides-producing
flora are reduced in number within the mucosal barrier of the
respiratory and gastrointestinal tracts, thus facilitating the
penetration of pathogens and increasing the risk of infection.57
When pathogens cross the first line of defense, the innate
immune response is triggered through several pathways. This
innate immune response is partial in preterm and LBW infants
due to availability of smaller number of neutrophils compared to
full-term and normal birth weight infants. Neutrophils generate
oxygen radicals that facilitate intracellular killing of pathogens
and can also perform phagocytosis.55,56,58 Similarly, a smaller
pool of monocytes is available in preterm and LBW infants.
Table 1. Vaccination recommendations and overview of availability of immunogenicity and safety of recommended vaccinations for preterm and LBW infants ≤12 months of age.
Immunogenicity/Effectiveness Safety
Preterm
Recommended Europe USA Australia Included in the Age (chronological age) recommendation in Preterm LBW (<2,500 (<37 weeks) LBW (<2,500
- ±
VaccineIt by WHO24 (ECDC)Ɣ25 (CDC)26,27 Canada28 (ATAGI)Ƙ29 India (IAP)21 Indian NIP22 India21,22 (<37 weeks) ± grams) ± grams) ±
BCG Yes Yes$ n.a n.a n.a Yes Yes At birth or as early as possible till one year of Yes30 Yes30 Yes30 Yes30
age
Hepatitis B Yes Yes Yes Yes Yes Yes Yes First dose at birth or as early as possible Yes31,32 Yes23,31 Yes31,32 Yes23
within 24 hours
OPV – 0 Yes n.a n.a n.a n.a Yes Yes At birth or as early as possible within the Yes33 n.a. Yes33 n.a.
first 15 days
34 34
OPV – 1, 2, 3 Yes n.a n.a n.a n.a Yes, At 6 weeks and 14 weeks, in case Yes At 6 weeks, 10 weeks and 14 weeks (OPV Yes n.a. Yes n.a.
IPV not available or feasible can be given till 5 years of age)
Fractional IPV Yes Yes Yes n.a n.a Yes Yes Two fractional doses at 6 and 14 weeks of Yes35,36 n.a. Yes36 n.a.
age
Pentavalent combination n.a Yes n.a n.a n.a Yes Yes At 6 weeks, 10 weeks and 14 weeks (can be n.a. n.a. n.a. n.a.
(DTaP-Hib-Hep B) given till one year of age)
37,38 37,38 37,38
Hexavalent combination (DTaP- n.a Yes n.a Yes Yes No n.a. Yes Yes Yes Yes37,38
Hib-IPV-Hep B)
PCV Yes Yes Yes Yes Yes Yes Yes (select At 6 weeks and 14 weeks. Booster dose at Yes (PCV7, PCV10, Yes (PCV7, Yes41 Yes39
states) 9–15 months of age. PCV13)39–41 PCV10)39,40
Rotavirus Yes Yes Yes Yes Yes Yes Yes (select At 6 weeks, 10 weeks & 14 weeks (can be Yes42–45 n.a. Yes42–45 n.a.
states) given till one year of age)
Influenza No No n.a Yes Yes Yes No 6 months–5 years Yes46 Yes46 Yes46 Yes46
Measles, mumps, rubella, n.a Yes Yes Yes Yes Yes Yes 9 months-12 months n.a. n.a. n.a. n.a.
varicella£
-It
Vaccinations should be administered to preterm and LBW infants according to the recommended schedule at the discretion of the physician
Ɣ
The data presented in the Table is a comparison of recommendations for the UK and Germany
Ƙ
For preterm infants only
±
Limited evidence in infants with a gestational age of<31 weeks and very LBW infants
$
For infants in areas of the country with TB incidence ≥ 40/100,000. Infants with a parent or grandparent born in a high incidence country
£
Individual vaccine recommendations are reported for measles, mumps, rubella and varicella vaccines and not combination vaccines
ATAGI: Australian Technical Advisory Group on Immunization; BCG: Bacillus Calmette-Guerin vaccine; CDC: Centers for Disease Control and prevention; ECDC: Europe Centre for Disease prevention and Control; IAP: Indian Academy
of Pediatrics; NIP: National Immunization Program; LBW: low birth weight; TB: tuberculosis; OPV: oral polio vaccine; IPV: inactivated polio vaccine; DTaP: diphtheria, tetanus, pertussis vaccine; Hib: Hemophilus influenza type b; Hep
B: hepatitis B; PCV-7, −10, −13: pneumococcal conjugate vaccine, −7 valent, −10 valent and −13 valent; MR: measles and rubella; MMR: measles, mumps, rubella; MMRV: measles, mumps, rubella with varicella; n.a.: not available;
WHO: World Health Organization
HUMAN VACCINES & IMMUNOTHERAPEUTICS
e1866950-3
e1866950-4 S. SOANS ET AL.
Figure 1. Plain language summary.
Monocytes are capable of phagocytosis, secretion of cytokines or
chemokines and antigen presentation, and regulate the activa­
tion of B-cells and T-cells, which are integral parts of the adap­
tive immune response.55,56 Consequently, preterm and LBW
infants are at a high risk of infection (Table 2).
Intrauterine inflammation, which may cause premature
immune activation and cytokine production, directly contri­
butes to preterm birth,56 and may lead to immune tolerance
and reduced immune function in preterm and LBW newborns.
Furthermore, medical interventions at the time of delivery can
impact immune development and function. For example,
antenatal corticosteroid treatment to prevent newborn respira­
tory disease is associated with reductions in lymphocyte pro­
liferation, cytokine production and an increased risk of
infection.56
Soluble proteins such as immunoglobulins (Ig) and pep­
tides facilitate phagocytosis and elicit antimicrobial proper­
ties. The production of soluble proteins by the fetus is
limited and thus adaptive immunity is mostly provided
through maternal antibodies. Maternal IgG antibodies are
transferred to the fetus starting at approximately 17 weeks
of gestation, with cord-blood IgG levels similar to maternal
titers after 32 weeks of gestation and up to 2-fold higher at
term birth.59,60 Due to this, preterm infants have low levels
of circulating maternal IgG as a function of gestational age
at birth. This leads to a higher susceptibility of infants to
contract infections, including those that can be prevented
by vaccinations.59,61
VPDs in preterm and LBW infants
Newborns usually contract infections either in the perinatal or the
postpartum period. Exposure to infections is especially critical in
preterm and LBW infants because of their immature immune
system and inadequate levels of maternal antibodies.54–56,59 This
aspect is depicted in Figure 2A for reference. Data on the risk of
VPDs among preterm and LBW infants in India are lacking,
therefore we report information from other relevant countries
(Table 3). In comparison to full-term and normal birth weight
infants, preterm and LBW infants are at an increased risk of
hospitalization and mortality from VPDs such as diphtheria,62
influenza,68 invasive pneumococcal disease,39 bacterial
meningitis,66 pertussis,64,65,69 bacterial and viral pneumonia,66
rotavirus gastroenteritis67 and tetanus.63 Importantly, the litera­
ture suggests that an increased risk of infection positively
correlates with the degree of prematurity and LBW.66,70
Specifically, infection of the very and extremely LBW infants
with opportunistic and aggressive multidrug-resistant pathogens
often results in death.70
Vaccination programs and timing in preterm and LBW
infants
Published literature suggests that vaccination in preterm and
LBW infants is delayed despite the existence of
recommendations.47–50 Due to this, the risk of complications
and mortality from preventable infections is multiplied as the
susceptibility window to infections is increased from the time
of birth.69 Vaccination delay or refusal of vaccines for preterm
and LBW infants appears to be a prevalent issue in India as
documented from several studies.71–73 In these studies, delays
in timely vaccination for each vaccine was defined as adminis­
tration of the vaccine dose after 28 days of the minimum
recommended age, meaning that vaccination was categorized
as delayed if given on day 29 or later for Bacillus Calmette-
Guerin (BCG), 71 days or later (after 10 completed weeks) for
diphtheria-pertussis-tetanus (DPT)-first dose (DPT-1) and for
DPT–third dose (DPT-3), when the infant was vaccinated at
>18 weeks of age.71–73 For measles, delayed vaccination was
defined as having received the vaccine after 4 weeks of recom­
mended/due-time, i.e. after 9 completed months of age
(measles is recommended at 9 months of age).74 In the first
prospective study, almost half of the infants <33.5 weeks of
gestational age (very preterm) and weighing <1,500 g (very
LBW) were without immunization, while 62.5% of the remain­
ing infants had a documented delay in immunization.72 In
the second study, data from the National Family and Health
Survey-4 revealed that LBW infants with a birth weight <2,000
g had higher odds of a delay in receiving the BCG vaccine
(adjusted odds ratio [aOR] 2.33, 95% confidence interval [CI]
1.89, 2.89) and the DPT-1 (aOR 1.53, 95% CI 1.26, 1.86) and
the first dose of the measles vaccine (aOR 1.36, 95% CI 1.11,
1.67).71 In a third study, in which 10,644 LBW infants (<2,500
g) were enrolled and followed until 12 months of age, a sig­
nificantly lower immunization uptake was documented both in
terms of the proportion of infants immunized and of the
timing of vaccine administration (Figure 3). About 3 out of
10 LBW infants were fully immunized by the age of 1 year (i.e.,
had received the BCG vaccine, three doses of the DPT vaccine,
the oral polio vaccine, and the measles vaccine).73 There was
a delay in the time of administration of the vaccines compared
to the recommended timing. The median delay (interquartile
range) for the BCG vaccine was 41 (19–75), and for the three
doses of the DPT vaccine (DPT–1, DPT–2 and DPT–3) was 30
(12–63), 46 (23–89) and 62 (34–112) days, respectively.73 For
the measles vaccine, the median delay from the recommended
timing was 24 (9–46) days.73
Barriers to vaccination in preterm and LBW infants
Overall in India, several barriers to infant vaccination according to
the recommended schedule have been documented. Vaccine hes­
itancy was a common barrier across different age groups.52,75,76
Table 2. Characteristics of the immune response in preterm and LBW infants10,54–56.
Type of immune response Role at nominal level Characteristics in preterm and LBW infants
Innate immunity
Soluble proteins and peptides10,56 ● Able to opsonize pathogens thus aiding phagocytosis and kill patho­ ● Limited production leads to preterm infants experiencing limited exposure to breast milk that contains
gens with their antimicrobial properties antimicrobial peptides
IgG ● Protective antibody against viruses, bacteria and anti-toxins ● Limited production
● Low levels of maternal IgG (increases with fetal age)
APPs10,56 ● Destroy pathogens via diverse mechanisms ● Reduced production in preterm infants and reduced exposure through breast milk
BPI55 ● Neutralizes the lipopolysaccharide endotoxin and is cytotoxic to gram ● Found at lower concentrations in preterm infants
negative bacteria
NK cells55 ● Produce cytotoxicity and lyse infected cells or antibody-sensitized ● Lower activity
cells ● Reduced number of cells compared to full-term infants
Classical, alternative and lectin ● MBL is a well characterized activator of the lectin pathway in anti­ ● Reduced pathogen-killing abilities
complement pathways54–56 body deficient neonates ● Deficient in production of C1, C4 (classical pathway) and factor B (alternative pathway)
● L-ficolin is a major pattern recognition molecule involved in activa­ ● Deficient in pattern-recognition receptor MBL
tion of the lectin pathway ● MBL could be associated with particular deleterious effects in preterm infants
● Low production of GM-CSF and G-CSF hormones
● L-ficolin production and function reduced
Phagocytes54 ● Include neutrophils, monocytes and macrophages ● Limited chemotaxis of phagocytes to infectious sites
Neutrophils10,55 ● Phagocytose and destroy microorganisms intracellularly by utilizing ● Have reduced pool including precursors due to reduced glycoprotein hormones G-CSF and GM-CSF
a variety of toxic substances ● difficulty in migrating to sites of infection due to reduction in expression of adhesion molecules such as L –
and P-selectin
● Decreased phagocytic activity of preterm neutrophils
● Preterm neonates have decreased respiratory burst
● Reduced expression and inducibility of integrins or arrest of cell-rolling and adhesion
Monocytes10,55,56 ● Phagocytose and destroy microorganisms intracellularly by utilizing ● Smaller pool of monocytes due to reduced glycoprotein hormones G-CSF and GM-CSF
a variety of toxic substances ● Reduction in cytokine production
● Differentiate into macrophages or dendritic cells in tissue ○ Low levels of chemotaxis and phagocytosis during infection
○ Reduced ability of costimulatory molecules upregulation
○ Limited capacity to activate B – and T-cells
● Adaptive immune response activation is limited
Adaptive immunity
Overall - ● Maturation of this type of immunity occurs mostly after term birth
● All newborns have deficiencies in T-cell activation, cytokine production, cytolytic activity, B cell immu­
noglobulin production, and cooperation between T and B-cells
Circulating lymphocytes (B and ● Produce or express cytokines and IgM antibodies ● Lower absolute numbers
T-cells)10,54 ● Lower numbers of naïve T – and B-cells
● Lower IgG concentrations
T lymphocytes helper (CD4+)55 ● Respond to new antigens by producing or expressing cytokines in ● Decreased stimulation of B-lymphocytes to produce antibodies
their cell membrane
● Activated by MHC class 2
55
Cytotoxic lymphocytes (CD8+) ● Eradicate lysed cells through clonal expansion of antigen-specific ● Decreased cytotoxic activity
cytolytic cells ● Lower absolute numbers of CD3 and CD8 cells
● Activated by MHC class 1
HUMAN VACCINES & IMMUNOTHERAPEUTICS

APP: antimicrobial proteins and peptides; BPI: bactericidal permeability increasing protein; CD: cluster of differentiation; IgG: immunoglobulin G; IgM: immunoglobulin M; LBW: low birth weight; MBL: mannose-binding lectin;
G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; MHC: major histocompatibility complex; NK: natural killer
e1866950-5
e1866950-6 S. SOANS ET AL.

Figure 2. Vaccination in preterm and LBW infants in India (A) Window of susceptibility to disease (B) Barriers to vaccination due to knowledge gaps among HCPs and
parents ± ‡. *Immune response refers to sero-conversion/sero-protection levels±Vaccination recommendations in the National Immunization Programme (Government
of India)22 and Indian Academy of Pediatrics (optional schedule)21 is provided in Table 1 ‡Panel B was created from Table 1 of Sahoo et al. 2020,53 and the personal
opinions of the authors of this manuscript; HCP: healthcare professional; LBW: low birth weight

Several factors were identified as causes of vaccine hesitancy in
India: these relate to immunization effectiveness, safety/adverse
events, provider belief, attitudes of parents, religious/socioeco­
nomic factors, and policy guidelines regarding vaccination.52,75
These factors become even more complex in preterm and LBW
infants.53,71–73 Factors of delayed vaccination in preterm and LBW
infants were identified in two studies.71,73 Choudhary et al. and
Upadhyay et al. both reported that Islamic religion and young
maternal age (<20 years of age) were associated with lower odds of
full immunization and higher odds of delayed vaccination for
DPT–1. Female sex of the infant, birth weight <2,000 g, delivery
by unskilled personnel, higher number of children and a lack of
awareness about vaccination risks/benefits among mothers were
also associated with lower odds of full immunization. In contrast,
a high level of maternal education was strongly associated with
improved vaccination status of the infant.71,73 Across studies, the
main reason for a delay in vaccination was the general lack of
awareness among HCPs and parents about vaccination benefits
and concerns about possible adverse events due to vaccination in
preterm and LBW infants.71–73,76 To this, we suggest the use of
vaccines with published efficacy and safety data in the preterm and
LBW infant population (Table 1).
Despite the availability of evidence and clear guidelines related
to vaccination in India,21,22 there are wide knowledge gaps among
HCPs and parents regarding the safety and efficacy of vaccines.53
Further details can be seen in Figure 1B. Several factors were found
to influence the attitude of HCPs toward vaccination for preterm
and LBW infants. These include the perception of limited vaccine
effectiveness, the risk of vaccination-induced serious adverse
events and contraindication following postnatal steroid
administration.56 HCPs further perceive that birth weight, current
weight, or the level of prematurity should determine the initiation
 HUMAN VACCINES & IMMUNOTHERAPEUTICS e1866950-7

Table 3. Risk of vaccine-preventable disease in preterm and LBW infants.

Disease Outcome Risk of acquiring disease
Diphtheria ● Increased riskƘ of disease62 n.r.¥
Tetanus ● Death due to neonatal tetanus in LBW OR: 2.09 (95%CI: 1.29–3.37)63
Pertussis ● Hospitalization in preterm vs. full-term infants IRR: 1.99 (95%CI: 1.47–2.71)64
● Severe disease with a history of prematurity OR: 5.00 (95%CI: 1.27–19.71)65
Polio ● Increased risk of disease n.r. ¥
Hepatitis B ● Increased risk of disease n.r. ¥
Invasive pneumococcal disease ● Risk of infection in LBW (<2,500 grams) infants RR: 2.6 (P = .03)39
● Risk of infection in preterm (<38 weeks) infants RR: 1.6 (P = .06)39
Bacterial meningitis ● Hospitalization in infants weighing <1,000 grams RR: 1.38 (95%CI: 0.57–3.35)66
● Hospitalization in infants weighing 1,000–1,499 grams RR: 1.46 (95%CI: 0.88–2.44)66
● Hospitalization in infants weighing 1,500–1,999 grams RR: 1.55 (95%CI: 1.13–2.12)66
● Hospitalization in infants weighing 2,000–2,499 grams RR: 1.31 (95%CI: 1.09–1.58)66
Bacterial pneumonia ● Hospitalization in infants weighing <1,000 grams RR: 2.86 (95%CI: 1.83–4.47)66
● Hospitalization in infants weighing 1,000–1,499 grams RR: 1.67 (95%CI: 1.20–2.33)66
● Hospitalization in infants weighing 1,500–1,999 grams RR: 1.53 (95%CI: 1.22–1.91)66
● Hospitalization in infants weighing 2,000–2,499 grams RR: 1.51 (95%CI: 1.32–1.71)66
Rotavirus gastroenteritis ● Hospitalization in very LBWs (<1,500 grams) OR: 2.6 (95%CI: 1.6–4.1)67
● Hospitalization in LBW (1,500–2,499 grams) OR: 1.6 (95%CI: 1.3–2.1)67
Influenza ● Severe disease in children with history of prematurity OR: 2.53 (95%CI: 1.34–4.77)68
Ƙ
Age data reflect a higher proportion of cases in the adolescent and adult populations. These populations could be the source of infection in preterm and LBW infants
¥
No data was found for these diseases. It can be assumed that there is a high risk of these diseases occurring given the immaturity of the immune system of the preterm
and LBW infant
CI: confidence interval; IRR: incidence rate ratio; LBW: low birth weight; OR: odds ratio; P: p-value; RR: relative risk

is known to be challenging.70 While the majority of

Figure 3. Immunization delay among LBW infants±‡. ±Statistically significant
difference (P < .05) compared to normal birth weight infants was documented for
all vaccines. Vaccination was administered according to the National Immunization
Programme (Government of India). BCG and OPV-0 at birth,
OPV-1/DPT-1 at 6 weeks of age, OPV-2/DPT-2 at 10 weeks of age, OPV-3/DPT-3
at 14 weeks of age and measles at 9 months of age.21,22 Delayed vaccination for
each vaccine was defined as administration of the vaccine dose after 28 days
(i.e. 4 weeks) of the minimum recommended age, as per the National
Immunization Programme (Government of India).22 ‡Created from Table 2 of
Upadhyay et al. 2017.73 The reported data were obtained from the rural Haryana
region BCG: Bacillus Calmette-Guerin vaccine; DPT: diphtheria, pertussis, tetanus
vaccine; OPV: oral polio vaccine; LBW: low birth weight; NBW: normal birth weight
infants will have some risk factors, there are several pre­
senting symptoms that are nonspecific.70 Therefore, it has
become imperative to prevent the burden of infectious
diseases in preterm and LBW infants. This can be
achieved using a two-fold strategy targeting both mothers
and their newborn infants.
It is vital to reduce the risks of infection in premature
infants through prevention of infections in expectant
mothers. It is essential to implement a comprehensive
strategy comprising multiple elements such as improving
maternal nutritional status, diagnosing and treating preg­
nancy-related conditions, and providing adequate mater­
nal and perinatal care. The prevention of infections
through immunization activities, which are known to be
effective in circumventing the risks associated with VPDs,
should also be encouraged.24 Several immunization strate­
gies have been suggested for the protection of newborn
infants, the features of which are further discussed.

of immunization.50 The lack of clear vaccination recommenda­

tions from HCPs ultimately guides the decision of parents or
caregivers of the infant to reject vaccinations.77 Even if there are
clear recommendations, a low education level and awareness of the
parent or caregiver could delay vaccination or lead to refusal.72,76,77
In India, a lack of education for girls and young women, who are
socially viewed as the primary caregiver, could undermine immu­
nization efforts.76 Other factors such as home births in India71 and
the cost of vaccination73 also tend to qualify as impediments to the
vaccination of preterm and LBW infants.
Strategies to mitigate the burden of VPDs in preterm
and LBW infants
Successful treatment of infections in preterm and LBW
infants relies on early recognition and diagnosis, which
Indirect immunization strategies
The use of indirect immunization strategies such as maternal
immunization and cocooning have been suggested as relevant
strategies to alleviate the burden of VPDs in infants (e.g.
tetanus, pertussis, influenza etc.).24,63–65,78 Vaccination during
pregnancy (maternal immunization) can provide protection
against VPD for the mother, the developing fetus and the
newborn through maternal antibodies transfer via the placenta
and subsequently the breast milk.79 An example is neonatal
tetanus, which tends to occur during the first 3–14 days of life
and which carries a case fatality rate of 100% in newborns.
Through immunization efforts, maternal and neonatal tetanus
have been eliminated from India.80 Pertussis and influenza are
other preventable diseases with potentially severe conse­
quences (such as apnea, pneumonia and seizures in newborns)
e1866950-8 S. SOANS ET AL.
that can be averted through maternal immunization.78,81
Maternal immunization provides clear benefits. It is worth
noting that the uptake of maternal immunization can however
be slow.82,83 Common reasons include issues of confidence
(i.e., fear of adverse pregnancy outcomes, lack of awareness,
failure of the HCP to recommend vaccination and conveni­
ence/access [including cost]) and vaccine efficacy, driven pos­
sibly by the timing of vaccination.82–84
Recent studies have suggested that antigen-specific cord-
blood antibody titers are greater following maternal immuni­
zation with the tetanus, diphtheria, and acellular pertussis
vaccine in the second, rather than the third trimester.85,86 For
influenza vaccination, researchers have shown that seasonal
influenza vaccination should be given at any stage of preg­
nancy, with the caveat that it takes 2 weeks after vaccination
for the mother to be protected against influenza.87–90 Public
health authorities have also revised their recommendations,
with a few of them even recommending vaccinations as early
as possible during pregnancy.89,90 Further research efforts to
establish the appropriate timing of vaccinations during preg­
nancy could strengthen the use of maternal immunization in
preventive neonatology.84
Other indirect immunization strategies such as cocooning
could be considered when maternal immunization is missed or
delayed. The IAP recommendation states that immunizing
individuals who have regular contacts with a newborn might
help reduce the risk of infection in newborns.78 However, there
is little evidence to support the use of this strategy in protecting
the extremely preterm and LBW infants. Additionally, cost and
logistical barriers could further limit the widespread imple­
mentation of this strategy.91,92
Direct immunization of preterm and LBW infants
In preterm and LBW infants, implementing the same vaccina­
tion schedule as set forth for full-term and normal birth weight
infants appears crucial, as can be seen in the vaccination
recommendations (Table 1). Specific guidance regarding the
implementation of vaccination when the infant is in the neo­
natal intensive care unit (NICU) is not explicitly mentioned in
the guidelines; there is limited evidence to suggest that vacci­
nation could be considered in the NICU if the infant is stable or
after discharge from the NICU in the ward.93 Table 1 also
provides an overview of the main references that provide
immunogenicity/efficacy, effectiveness and safety data for the
recommended vaccinations specific to the preterm and LBW
infant population. This evidence base supports the vaccination
of infants regardless of prematurity level or birth weight at the
recommended chronological age according to the vaccine-
specific prescribing information.
Across the different vaccinations, the degree of immune
response may vary in terms of geometric mean titers in pre­
term infants, but protective and durable responses are achieved
in most cases.94,95 Studies have shown that, following admin­
istration of vaccines, preterm and LBW infants mount an
immune response directly proportional to their gestational
age and birth weight.96 Importantly, vaccines display a good
safety profile even when given in combination, without com­
promising the immune response; this could potentially
alleviate concerns of parents or HCPs with respect to safety.97
In addition, vaccinations recommended for use in healthy
infants and children have shown good levels of efficacy, safety,
and effectiveness regardless of prematurity or birth weight
(Figure 1B).
Among the combination vaccines available, the diphtheria,
tetanus, pertussis, hepatitis B, inactivated polio vaccine and
Hemophilus influenzae type b (DTPa-HBV-IPV/Hib), given
alone or with other pediatric vaccines, has a clinically acceptable
safety and immunogenicity profile in preterm (>24 weeks) and
LBW (as low as 700 g) infants as in full-term infants, although
HBV and Hib vaccine responses appeared lower in preterm and
LBW infants.37 The occurrence of post-immunization cardior­
espiratory events is influenced by the severity of underlying
neonatal conditions, but most tend to resolve spontaneously or
require minimal intervention.37 These data make a strong case
for the vaccination of preterm and LBW infants according to the
schedule proposed for full-term and normal birth weight infants
(i.e., chronological age). However, monitoring of the preterm/
LBW infant up to 72 hours after vaccination is recommended.98
Notably, additional doses of HBV should be administered in
infants receiving the first dose during the first days of life if they
weigh less than 2,000 g because of a reduced immune response;
for preterm infants born to hepatitis B Ag-positive mothers, both
Ig and HBV should be given within 12 hours.24,31,99 The time­
liness of vaccination and completion of the primary vaccination
series at chronological age rather than gestational age appears
crucial to provide the earliest possible protection in preterm and
LBW infants.95 Importantly, we suggest the use of vaccines that
have been tested in the preterm and LBW infant population and
have robust efficacy and a clinically acceptable safety profile.
Discussion
The considerations presented in this review have both clin­
ical and public health implications for India. In recent dec­
ades, India has seen a significant improvement in neonatal
and infant health after the introduction of several initiatives
by the Government of India (GOI).51 India’s National
Health Policy 2017 set a target of 16 deaths per 1,000 live
births for neonatal mortality by 2025,100 and the GOI has
also set a target of less than 10 neonatal deaths per 1,000 live
births by 2030 under the India Newborn Action Plan.101
Within this context, prematurity and LBW in neonates
deserve special attention, as a significant number of children
born in India are born preterm or have LBW.14,19 Although
a systematic literature search was not included in this
review, which is a limitation, it reaches its objective of
raising awareness on the importance of reducing the inci­
dence of VPDs in preterm and LBW infants in India through
immunization.
Published evidence from studies conducted outside India
indeed shows that prematurity and LBW can predispose the
infant, given their immunocompromised status, to a high risk
of VPDs.54,56,69,96,102 Reducing the incidence of VPDs in this
vulnerable population after birth is the need of the hour. This
can be achieved through timely immunization of the mother
and newborn. Maternal immunization should be encouraged
and there is a large evidence base supporting the safety and

effectiveness of immunization during pregnancy.84,103
Similarly, vaccines in preterm and LBW infants are equally
safe, immunogenic and effective as compared to full-term
and normal birth weight infants.94–96 Generating more evi­
dence on the timing of maternal immunization, as well as
identifying and addressing barriers to vaccination uptake, are
key challenges to overcome.84,88
In India, healthcare institutions advocate that preterm and
LBW infants are vaccinated following the same schedule as that
of their counterparts who are born full-term with normal birth
weights, apart from the hepatitis B vaccine wherein an addi­
tional dose is required.21–23 Notwithstanding these recommen­
dations, studies from India show that preterm and LBW infants
are vaccinated with a significant delay,71,73,76 driven by the
clinical judgment of the treating HCP whose recommendation
is instrumental in ensuring vaccination. Delays due to true
contraindications (e.g., severe combined immunodeficiency
disease) are justified, but avoiding risks related to ‘small for
gestational age’ or birthweight are often cited as the reason
behind vaccination delays. LBW appears to be a strong indi­
cator of vaccination delay. Given that being born preterm is
a leading cause of LBW, gestational age could also be recog­
nized as a predictor of vaccination delay.50 Data specific to
vaccination delays in premature infants from India are lacking
and are needed to shape the national vaccination policy. In
addition, information assessing the relationship between vac­
cination delay and disease occurrence should be generated
through large-scale observational studies. Further studies esti­
mating vaccination coverage in preterm and LBW infants
might provide insights on the scale of the problem and the
underlying reasons for vaccination delay.
Delayed vaccination increases the susceptibility window to
VPDs and their complications.50 There are several barriers in
achieving timely vaccination of preterm and LBW infants in
India. Among these, HCP and parent knowledge, perceptions
and attitudes to vaccination stand out. The role of HCPs in
facilitating immunization uptake is well-documented hence
training HCPs to discuss the risks versus benefits of vaccina­
tions with parents, on scientifically validated grounds, seems
highly relevant.50,77 To achieve this, HCPs must regularly
acquire up-to-date information on vaccinations in preterm
and LBW infants. Besides efficacy and safety, parents tend to
worry about the number of vaccinations.53 Targeted education
and awareness initiatives for HCPs and health literacy inter­
ventions for parents, with focus on the importance, effective­
ness and safety of vaccinations could help bridge immunization
gaps in the vulnerable preterm and LBW infant population. In
addition, the use of combination vaccines should be encour­
aged, as it addresses parents’ fears of multiple injections and
increases the acceptance and compliance with the vaccination
schedule.97
Conclusion
Routine childhood vaccinations can help reduce or eliminate
the burden of VPDs and should be given to preterm and LBW
babies, regardless of prematurity or birth weight. It is crucial
that HCPs are made aware that preterm and LBW infants could
be faced with detrimental health effects if vaccinations are not
HUMAN VACCINES & IMMUNOTHERAPEUTICS e1866950-9
administered in a timely manner. Inappropriate delays in vac­
cinating this fragile population should be minimized by ensur­
ing that vaccination discussions are encouraged with families
and caregivers at the point of care. These steps should be
closely integrated within neonatal and other overall infant
health management strategies to increase vaccination compli­
ance and improve health in the fragile population of preterm
and LBW infants.
Acknowledgments
The authors thank Business & Decision Life Sciences platform for editorial
assistance and manuscript coordination, on behalf of GSK. Benjamin
Lemaire coordinated the manuscript development and editorial support.
Amrita Ostawal (Arete Communication UG) provided medical writing
support.
Disclosure of potential conflicts of interest
Santosh Soans declares no financial and non-financial relationships and
activities and no conflicts of interest. Attila Mihalyi, Valerie Berlaimont
and Shafi Kolhapure are employees of the GSK group of companies, hold
shares in the GSK group of companies and declare no other financial and
non-financial relationships and activities. Resham Dash and Ashish
Agrawal are employees of the GSK group of companies and declare no
non-financial conflicts of interest.
Contributorship
All authors participated in the design of this narrative review, interpreta­
tion of the results; and the development of this manuscript. All authors
had full access to the data and gave final approval before submission.
Funding
GlaxoSmithKline Biologicals SA took in charge all costs associated with
the development and publication of this manuscript.
ORCID
Valerie Berlaimont http://orcid.org/0000-0003-3850-4477
Shafi Kolhapure http://orcid.org/0000-0002-3183-1259
Resham Dash http://orcid.org/0000-0002-0332-5535
Ashish Agrawal http://orcid.org/0000-0002-6417-3184
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